DESCRIPTION (Applicant's Abstract): In recent years, numerous peptides have been synthesized with high affinity and selectivity for the different types (mu, delta, kappa) of opioid peptides. These opioid receptor-specific peptides have unique pharmacology properties that warrant their development as therapeutic agents. However, in many cases, the clinical development of these opioid peptides has been prevented because of their poor biopharmaceutical properties [e.g., permeation across the intestinal mucosa and blood-brain barrier (BBB)]. During the first two years of this NIDA grant, we have demonstrated that cyclic prodrugs of opioid peptides in general have significantly better cell permeation characteristics than do the opioid peptides themselves. The major objectives of this renewal application include: (i) to demonstrate that the cyclic prodrugs have better oral bioavailability and better permeation of the BBB in vivo than the opioid peptides; (ii) better define how the structure of the "chemical linker" used to cyclize the peptide and the structure of the opioid peptide, itself, influence the permeation characteristics of the prodrugs, particularly their substrate activity for efflux systems (P-glycoproteins), which have been shown to limit their permeation through the intestinal mucosa and the BBB; and (iii) to optimize the bioconversion rates of the prodrugs to the opioid peptides in vivo in order to maximize their pharmacological effects. These studies should lead to the identification of the optimal structural features of the chemical linkers that when employed to make cyclic prodrugs of opioid peptides will afford optimal pharmacological effects after i.v. or p.o. administration.